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1

Targeting mitochondria in Alzheimer’s disease: effects of omega 3 fatty acids

100%

Eckert A.

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tom 73

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nr Suppl.1

EN

Increasing evidences suggest that mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD). Alterations of mitochondrial efficiency and function are mainly related to failure of enzyme activities of mitochondrial complexes from the electron transport chain leading to oxidative stress, deficits in cellular bioenergetics and finally neuronal death. More recently, structural changes of the mitochondrial network were related to bioenergetic dysfunction, and the consequences are a matter of intensive research. The essential role of mitochondrial bioenergetics and the unique trajectory of alterations in brain metabolic capacity enable a bioenergetic- centric strategy that targets disease-stage specific pattern of brain metabolism for disease prevention and treatment. Recently, high fish intake or dietary supplementation with omega-3 fatty acids (n-3 FAs) has been linked to reductions in the risk of developing AD and to delayed cognitive decline in patients with very mild AD. However, the underlying cellular and molecular effects of n-3 FAs are poorly described. Here, we present new data demonstrating protective effects of n-3 FAs on bioenergetic function. Since mitochondrial dysfunction represents an early event in disease progression, more studies are needed that focus on therapeutic strategies starting before severe progression of the disease.

2

The relationship between mitochondria function and circadian clock in peripheral oscillators

45%

Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

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tom 73

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nr 1

EN

Circadian rhythms govern a wide variety of physical, behavioral and metabolic changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. These are controlled by the circadian clock mechanism, where rhythm-generating mechanism is encoded by a transcription-translation feedback loop. Numerous studies have pointed to a cyclic relationship wherein the rhythm impacts metabolic activity and metabolism feeds back to impinge upon the rhythm. Mitochondria play a pivotal role in regulating cellular energy and were shown to be strategically positioned at the intersection between circadian rhythm and cell metabolism. Nevertheless little is known about their function in controlling the circadian rhythm. In our study, we investigated the involvement of circadian clock in mitochondrial function as well as mitochondria-dependent regulation of circadian clock. The study was carried out in primary human fibroblasts, an already established model to investigate molecular clock mechanisms in vitro. We have found that mitochondria activity as well as network activities showed rhythmic changes within 24 hours. Circadian pattern was detected for mitochondrial ROS including superoxide anion production. A significant 24-hour oscillation was found for cellular redox state. Furthermore, mitochondrial ATP levels were rhythmic and the maximum of ATP production paralleled the peak of mitochondrial ROS level and the mitochondrial network formation. Circadian rhythm was also detected for calcium ions concentration. Increase of ATP synthesis as well as changes in calcium and ROS level activated AMP-dependent protein kinase (AMPK). We have found that in primary human fibroblasts AMPK protein level and activity fluctuate in an antiphase relationship with rhythmic ATP production. Summarizing, our data provide the evidence for circadian regulation of mitochondrial dynamics and suggest that changes of mitochondrial activity may directly influence cellular clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E

3

Alzheimer’s amyloid beta peptides disturb circadian oscillations of intracellular calcium concentration

45%

Kazmierczak A. , Schmitt K. , Grimm A. , Strosznajder J. B. , Eckert A.

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tom 73

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nr 1

EN

It is postulated that disturbances in calcium homeostasis play an important role in pathogenesis of Alzheimer’s disease (AD). Changes of neuronal calcium concentration are responsible for the oxidative stress as well as altered metabolism and production of amyloid-beta peptides (Aβ). Aβ may further exacerbate calcium dysregulation, causing synaptic dysfunction, neurodegeneration and cognitive impairment. Recent data indicate that AD is associated with disturbances of circadian rhythm in the patients. However, till now nothing is known about the molecular mechanisms involved in AD-related circadian clock alterations. In our study we investigated the effect of Aβ peptides on the rhythmic oscillation of cytosolic and mitochondrial calcium levels. To investigate molecular clock mechanisms, the studies we carried out in human primary skin fibroblasts, a previously established experimental model. Our data showed circadian rhythm of calcium ions concentration in cytosol and mitochondria. Moreover we observed circadian oscillation of ROS formation and redox potential. Treatment with Aβ fibrils at the concentration of 0.5 µM disturbed cytosolic calcium oscillations and mitochondrial redox state. Studying mechanisms involved in this phenomenon indicated that Aβ did not affect ER calcium stores, but induced changes of calcium influx mediated by purinergic P2X7 receptor. The specific antagonist of P2X7 receptor Brillant Blue G abolished negative impact of Aβ and restored calcium circadian rhythm. Summarizing, our results indicate that Aβ may play a significant role in disturbances of circadian calcium oscillation, suggesting the importance of this phenomenon in ADrelated changes in biological clock. Supported by grants from Sciex 10. 258 to A.K. as well as Swiss National foundation (SNF No 310030_122572) and Synapsis Foundation to A.E.

4

Nitric oxide enhances expression and activity of cytosolic phospholipase A2 in PC12 cells with the different amyloid beta load

32%

Chalimoniuk M. , Stolecka A. , Haupmann S. , Schulz K. , Keil U. , Leuner K. , Eckert A. , Muller W. E. , Strosznajder J. B.

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2006

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tom 66

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nr 4

5

Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells

32%

Chalimoniuk M. , Stolecka A. , Cakala M. , Hauptmann S. , Schulz K. , Lipka U. , Leuner K. , Eckert A. , Muller W. E. , Strosznajder J. B.

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tom 54

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nr 3

EN

Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid β (Aβ) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and γ-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+]i and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Aβ peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.